COVID-19 cases, hospitalizations and deaths after vaccination: a cohort event monitoring study, Islamic Republic of Iran

Abstract Objective To investigate the incidence of coronavirus disease 2019 (COVID-19) cases, hospitalizations and deaths in Iranians vaccinated with either AZD1222 Vaxzevria, CovIran® vaccine, SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) or Sputnik V. Methods We enrolled individuals 18 years or older receiving their first COVID-19 vaccine dose between April 2021 and January 2022 in seven Iranian cities. Participants completed weekly follow-up surveys for 17 weeks (25 weeks for AZD1222) to report their COVID-19 status and hospitalization. We used Cox regression models to assess risk factors for contracting COVID-19, hospitalization and death. Findings Of 89 783 participants enrolled, incidence rates per 1 000 000 person-days were: 528.2 (95% confidence interval, CI: 514.0–542.7) for contracting COVID-19; 55.8 (95% CI: 51.4–60.5) for hospitalization; and 4.1 (95% CI: 3.0–5.5) for death. Compared with SARS-CoV-2 Vaccine (Vero Cell), hazard ratios (HR) for contracting COVID-19 were: 0.70 (95% CI: 0.61−0.80) with AZD1222; 0.73 (95% CI: 0.62–0.86) with Sputnik V; and 0.73 (95% CI: 0.63–0.86) with CovIran®. For hospitalization and death, all vaccines provided similar protection 14 days after the second dose. History of COVID-19 protected against contracting COVID-19 again (HR: 0.76; 95% CI: 0.69–0.84). Diabetes and respiratory, cardiac and renal disease were associated with higher risks of contracting COVID-19 after vaccination. Conclusion The rates of contracting COVID-19 after vaccination were relatively high. SARS-CoV-2 Vaccine (Vero Cell) provided lower protection against COVID-19 than other vaccines. People with comorbidities had higher risks of contracting COVID-19 and hospitalization and should be prioritized for preventive interventions.


Introduction
To end the ongoing global pandemic of coronavirus disease 2019 (COVID-19), it is imperative to have safe and effective vaccines that can provide immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. As of 10 June 2022, 364 vaccines against SARS-CoV-2 have been investigated, but only 37 of them have been used in Phase III clinical trials. 1 New vaccines are developed by companies and research centres using a broad range of techniques including viral vectors, inactivated vaccines, live weakened vaccines, deoxyribonucleic acid-(DNA) or ribonucleic acid-(RNA) based vaccines and protein-based vaccines. 2,3 Each technique has advantages and disadvantages. For example, viral vector vaccines trigger robust immune responses that can result in long-term protection; 4 however, they may also cause serious complications, such as immunity against the vector and coagulopathy. 5 Inactivated vaccines, on the other hand, while safe for immunocompromised individuals, 6 usually induce a much weaker immune response than viral vector-based vaccines. 7 As of 12 January 2022, the World Health Organization (WHO) lists only nine COVID-19 vaccines that have been deemed safe and efficacious for emergency use in national immunization programmes. 8 The approvals, however, are based on evidence from randomized controlled clinical trials whose samples may not necessarily be representative of the general population. Furthermore, only interim analyses were done for licensing purposes, the data did not allow the duration of protection to be determined and certain populations, such as pregnant women, were excluded. Therefore, active surveillance of the vaccines is needed through observational studies on the incidence of adverse events and COVID-19 cases and hospitalizations among vaccinated individuals over a defined period of time. To conduct an active safety surveillance study, a protocol template for cohort event monitoring studies has been released by WHO. 9 To meet the need for such data in the Islamic Republic of Iran for four COV-ID-19 vaccines (i.e. AZD1222 Vaxzevria, CovIran® vaccine, SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) or Sputnik V), we used the WHO protocol template for cohort event monitoring to design an observational study on the incidence of serious adverse events, adverse events of special interest and COVID-19 after each vaccine dose. We also sought to estimate the reactogenicity within 7 days of receiving each vaccine dose. 10 In this paper, we report the incidence of COVID-19 cases, hospitalizations and deaths among a vaccinated sample of the population. It should be noted that the objective of this study was to determine the safety and efficiency of each vaccine in terms of adverse events and COVID-19 and is in no way related to WHO emergency approval, nor does it reflect the opinions of WHO.

Methods
In accordance with the cohort event monitoring template developed by WHO, we conducted a four-arm cohort study in seven cities in the Islamic Republic of Iran (Birjand, Kerman, Mashhad, Rasht, Sanandaj, Shahroud and Zahedan). The selection of the study sites was based on availability of tertiary care hospitals and an experienced investigator and also on the commitment of local authorities to support the study. We invited individuals 18 years or older who were receiving their first dose of SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV), Sputnik V, AZD1222 Vaxzevria or CovIran® vaccine at a participating public vaccination site to participate. This study is part of a larger study, 10 and here we report the incidence of COVID-19 cases, hospitalizations for COVID-19 and deaths due to COVID-19 by vaccine brand. The study methods have been fully described previously 10 and we provide a summary as follows.
After enrolment, study staff interviewed the participants and collected their contact information and other data on vaccine brand, vaccination date, vaccine batch number, demographic characteristics (age, sex, years of education), previous COVID-19 and comorbidities (cancer, chronic cardiac, hepatic, men-tal, neurological, respiratory and renal diseases, diabetes, hypertension and immunodeficiency). To assess obesity, we also recorded self-reported weight and height and defined obesity as a body mass index ≥ 30 kg/m 2 . We actively followed participants until 3 months after their last dose of COVID-19 vaccine, if administered within 3 months of the first dose. For those receiving SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV), Sputnik V or CovIran® vaccine, the expected follow-up time was 17 weeks, assuming an interval of up to 1 month between the first and second doses. For those receiving AZD1222 Vaxzevria, given that the interval between doses is 3 months, the expected follow-up time was 25 weeks.
During the follow-up period, participants completed questionnaires through telephone or web-based surveys at weekly intervals. We also retrieved vaccination dates and vaccine batch numbers of the second doses from national COVID-19 vaccination registries. The diagnosis of COVID-19 infection was based on self-reported reverse-transcription polymerase chain reaction (PCR) test or antibodies against SARS-CoV-2. We also checked medical We considered participants lost to follow-up after two unsuccessful attempts to contact them by telephone, followed by one unsuccessful attempt to contact their next of kin. In case of loss to follow-up, we used data collected up to the last follow-up time in the analyses. We calculated the follow-up index (ratio) as the: actual investigated follow-up period/potential follow-up duration. 11 To factor in immunity status (time elapsed since vaccine dose administration), we considered the following immunity periods: non-immune period = first 14 days after the administration of the first dose; partial immunity period = period between 14 days after the first dose and 14 days after the second dose; full immunity period = period between 14 days after the second dose and the end of follow-up. We calculated incidence rates by dividing the total number of events by total person-days followed up, with their 95% confidence intervals (CI), for the total sample and by age, sex and immunity status. For the total follow-up period, we calculated incidence rates for events occurring 14 days after the first dose of the vaccine.
We used Cox proportional hazard regression models for survival analysis, with calendar time as the timescale and stratified by study sites to estimate the adjusted hazard ratios (HRs) for COVID-19 infection. We first used a univariate model with age, sex, education, vaccine brand, prior COVID-19 and comorbidities as covariates, and we only entered variables significant at P < 0.1 into the final stepwise Cox regression models.

Ethical considerations
The Institutional Review Board of Shahroud University of Medical Sciences, Islamic Republic of Iran (IR.SHMU. REC.1400.012) approved the study protocol, and we conducted all procedures in accordance with the Helsinki Declaration. Study participation was voluntary and all participants gave their written informed consent after trained staff had explained the study objectives and procedures and had answered participants' questions.

Results
Between 7 April 2021 and 22 January 2022, we enrolled 89 783 participants in the study (Fig. 1). Table 1 presents the distribution of participants by vaccine brand and vaccination status, demographic characteristics, underlying diseases and follow-up status. The follow-up index was more than 98% for all vaccines.
tions and deaths. Participants 50 years and older had significantly higher rates of hospitalization and death compared with those younger than 50 years regardless of vaccine brand. In addition, with all vaccine brands, both hospitalization and death rates were significantly higher during the partial immunity period than the full immunity period.
The results of Cox proportional hazard regression for COVID-19 infection are shown in Table 3. Sputnik V and AZD1222 Vaxzevria provided significantly greater protection than the SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) during the partial immunity period. In the full immunity period, the SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) provided lower protection than the other three vaccines. History of COVID-19 significantly reduced the risk of reinfection, and most underlying diseases signifi-cantly increased the risk of COVID-19, including chronic neurological disorders and mental health disorders. Table 4 shows the Cox proportional hazard regression for COVID-19 hospitalization. In the partial immunity period, AZD1222 Vaxzevria had significantly better effectiveness than the SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV), while in the full immunity period, no significant differences were found between vaccine brands. History of COVID-19 reduced the risk of hospitalization only in the partial immunity period. Most underlying diseases significantly increased the risk of COVID-19 hospitalization in the partial immunity period.
A total of 42 COVID-19-related deaths were registered; 17 (40.5%) occurred during the full immunity period (more than 14 days after administering the second dose). As such, the incidence of COVID-19 deaths per 1 000 000 person-days was 4.1 (95% CI: 3.0-5.5) overall (14 days after the first dose of vaccine till the end of follow-up) and 3.0 (95% CI: 1.9-4.8) during the full immunity period. The HR in the Cox regression model for COVID-19 death was not significantly different by vaccine brand in the full immunity period, but AZD1222 Vaxzevria provided better protection from death in the partial immunity period. Age (HR: 1.11; 95% CI: 1.04-1.17) and chronic renal diseases (HR: 5.13; 95% CI: 1.15-22.93) were associated with significantly higher risk of death (Table 5).

Discussion
Although vaccines provide adequate protection against SARS-CoV-2, their effectiveness never reaches 100%, and this protection is expected to further de-  12 In fact, all COVID-19 vaccines have waning protection. However, vaccinated individuals who do become infected experience less severe symptoms and have much lower risk of hospitalization and death compared with unvaccinated people with similar risk factors. 13 The results of our study showed overall breakthrough rates of 528.2, 55.8 and 4.1 per 1 000 000 person-days for COVID-19 cases, hospitalizations and deaths, respectively. The main determinants of breakthrough rates were: time since vaccination; the genetic variant of SARS-CoV-2; comorbidities; age; waning immunity; level of community adherence to mitigation strategies; and epidemic severity. 14 Therefore, it would be difficult to draw valid comparisons of breakthrough rates with other studies. For example, in Washington state in the United States of America, the rate of breakthrough infection among over 5 mil-lion fully vaccinated people increased from 1 per 5000 between 17 January and 21 August 2021, to 589 per 5000 between 17 January and 14 May 2022. 15 In addition, the comparison of different vaccine brands in our study is misleading because the participants entered the study at different calendar times when the severity stage of the epidemic and the dominant variant were different. A higher rate of breakthrough infection has been reported for delta variants of SARS-CoV-2. 16 The incidence of CO-VID-19 cases in fully vaccinated people was about 100 cases per 100 000 population in the United States during August to late November 2021 when the delta variant was the main variant. 17 The incidence of deaths related to COVID-19 was 0.38 per 100 000 among the same group and over the same time. In addition, during the week of 1 May 2021, the median number of incident cases of COVID-19 in New York State among the vaccinated population was 2.4 cases per 100 000 person-days (range 0.7 to 6.8). Rates increased after the delta variant became the most prevalent circulating variant and reached 16.4 cases per 100 000 person-days (range 8.3 to 27.9) among vaccinated people. 18 In our study, with 17 registered deaths (0.028% of admitted patients), the mortality rate in fully vaccinated people was 3.0 per 1 000 000 persondays; this rate is much higher than the rate reported in Massachusetts in the United States (0.01%) 19 but lower than Minnesota (0.032%). 13 Differences in age and COVID-19 epidemic patterns, virus variants, vaccine effectiveness and health-care utilization are the main reasons for differences between results and these factors should be noted when comparing study results.
The lower incidence rates of CO-VID-19 hospitalization and death in the full immunity period compared with the partial immunity period in our study are consistent with previous reports  on the effectiveness of COVID-19 vaccines. For example, analysis of National Immunization Management Service and the Coronavirus Clinical Information Network in the United Kingdom of Great Britain and Northern Ireland showed that out of 40 000 patients with COVID-19 who were admitted to hospital, 84% had not been vaccinated, 13% had only received their first vaccine dose and 3% had received both doses. 20,21 It should be noted that participants in our study were enrolled at different times on the epidemic curve. For example, the SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) became available just before the onset of the fifth COVID-19 wave, while CovIran® vaccine and SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) were the main brands used in the vaccination programme when COVID-19 incidence was at its peak in July 2021. Therefore, the occurrence of COVID-19 cases was affected by the time of entry of participants into the study. In addition, vaccines may lose their effectiveness over time as newer strains of the virus emerge. Even the age groups and comorbidities of participants varied by vaccine brands, and since the risk of infection differs by age and comorbidity, we cannot simply compare the incidence rates by vaccine brand. Thus, we used Cox regression analysis to adjust for important covariates and used calendar time as the time span.
Based on the results of the Cox regression analysis, AZD1222 Vaxzevria was most effective at preventing CO-VID-19 cases, hospitalizations and deaths, while the SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) had the lowest effectiveness, especially in the partial immunity period. A similar finding was recently reported in a large study conducted in the Islamic Republic of Iran. 22 The results suggest that vector-based vaccines (Sputnik V and AZD1222 Vaxzevria) had better effectiveness than inactivated vaccines (SARS-CoV-2 Vaccine (Vero Cell), Inactivated (lnCoV) and CovIran® vaccine).
The Cox regression models showed that individuals with chronic respiratory, renal and cardiac diseases, diabetes and obesity were at a higher risk of COVID-19 hospitalization, and a previous history of COVID-19 reduced this risk to less than half. Similar associations have been reported in other studies. 23,24 A study has shown that prior SARS-CoV-2 infection significantly reduces the risk of breakthrough infection. 25 Another factor associated with COVID-19 hospitalization was obesity. This outcome is most likely because obesity impairs immunity by altering the response of cytokines which increases susceptibility to infection, especially infections that require a rapid cellular immune response. 26,27 In addition, obesity is linked to metabolic disorders and  other critical diseases such as diabetes, hypertension, and cardiac and cerebrovascular diseases. Obesity and its related comorbidities have been shown to increase the cumulative risk of death in COVID-19 patients. 24,28 Similar to our findings, other studies confirmed the association of chronic neurological and mental diseases with contracting COVID-19. 29 Higher vulnerability to SARS-CoV-2 infection of participants with mental diseases may be attributed to their lower cooperation with preventive measures, which may also be true for people with dementia and Parkinson disease. However, more studies are needed to determine the exact reasons for the association between mental and neurological diseases and SARS-CoV-2 infection. 29 The main strengths of our study include its large sample size, the investigation and comparison of four vaccines, the active surveillance that was conducted, weekly follow-up of participants, and investigation and classification of all hospitalized participants. However, we could not determine virus variants and included no control group for investigating vaccine effectiveness, which can be considered limitations of our study.
In conclusion, COVID-19 breakthrough rates were relatively high in our study. AZD1222 Vaxzevria vaccine provided better protection from CO-VID-19 infection, hospitalization and death than the other three vaccines. All the vaccines had similar protection against COVID-19 hospitalization 14 days after the second dose. People with comorbidities had higher risk of contracting COVID-19 and hospitalization and should be prioritized for preventive interventions. ■